Selinexor Plus Ruxolitinib Displays Activity in Ruxolitinib-Pretreated Myelofibrosis

Selinexor (Xpovio) in combination with ruxolitinib (Jakafi) showed encouraging efficacy with a manageable safety profile in patients with myelofibrosis who previously received ruxolitinib, according to data from the phase 2 SENTRY trial (NCT04562389) presented during the 2024 ASH Annual Meeting.1

Preliminary findings from the study showed that, among efficacy-evaluable patients (n = 30), 26 patients (86.67%) experienced alleviation of their symptoms, 9 (40.91%) achieved a 50% reduction in either total symptom score (TSS) or clinical-assessed symptom response, and 1 (3.33%) achieved symptom resolution. Additionally, 4 of the 9 patients who were transfusion-dependent achieved transfusion independence after treatment with the combination.

“At ASH 2023, we presented promising efficacy and safety data in the real-world setting for selinexor in combination with ruxolitinib in patients with myelofibrosis. Here we will report the efficacy and safety of the regimen in patients in a prospective clinical trial who received prior treatment with ruxolitinib,” Minghui Duan, PhD, of the Department of Hematology at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College in Beijing, China, said during a presentation of the data.1,2

The prospective, open-label, multicenter phase 2 study enrolled a total of 38 patients.1 By July 2024, all 38 patients received at least 1 dose of selinexor, and at a 6-month analysis, 88% of patients had a reduction in spleen length and 36% achieved a spleen response, Duan stated. Spleen response was defined as a reduction in length that is more than 50% per the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet response criteria.

In total, there were 27 patients who received a 60-mg dose of selinexor, 10 who received a 40 mg dose, and 1 patient who received a 20-mg dose. The frequency of dose administration was weekly across all doses.

The primary end point of the trial was spleen response. This was assessed by palpation or CT and MRI. The secondary end points were anemia response, symptom response, and safety.

The median age across all patients was 65.5 years (range, 22-84), and 17 patients (44.74%) were male. The mean duration of prior ruxolitinib treatment was 20.5 months (range, 3.6-138.0).

Across all 38 patients, 25 (65.79%) harbored a JAK2 gene mutation, 5 (13.16%) had a CALR mutation, 1 (2.63%) had an MPL mutation, and 2 patients (5.26%) had triple-negative myelofibrosis. Data were missing for 3 patients (7.89%), and data for the remaining patients were unspecified. According to the Dynamic International Prognostic Scoring System model, 23 patients (60.53%) were classified as intermediate risk, 10 (26.32%) as high risk, and 5 (13.16%) as unknown. In addition, 36 patients (94.74%) had splenomegaly at diagnosis.

Regarding safety, the median treatment duration with selinexor was 151 days (range, 16–696), and this was consistent across both the 40-mg and 60-mg doses. In total, 18 patients discontinued treatment: 6 due to disease progression, 4 to enroll in another trial, 5 due to toxicity, 2 for economic reasons, and 1 to undergo transplantation. The most common any-grade adverse effects (AEs) were anemia and nausea (both 36.8%), followed by vomiting (23.7%). For grade 3 or 4 AEs, the most frequent were anemia (18.4%), thrombocytopenia (5.3%), and gastrointestinal symptoms, including nausea and vomiting (both 2.6%).

“Unlike the [phase 1] ESSENTIAL study [NCT03627403],” Duan began, which showed sustained spleen responses with selinexor as a single agent in myelofibrosis refractory to a JAK inhibitor, “this combination of selinexor and ruxolitinib may achieve similar therapeutic effects without requiring higher doses.” He also noted that “patients with myelofibrosis require more comprehensive methods for assessing efficacy than a 35% reduction in spleen volume or a 50% reduction in the total symptom score.”1,3

Phase 3 of the SENTRY trial is currently enrolling patients with myelofibrosis who are naive to a JAK inhibitor.

References

1. Duan M, Ma L, Wu Q, et al. The efficacy and safety of selinexor in combination with ruxolitinib in ruxolitinib-treated myelofibrosis patients: the interim analysis of a prospective, open-label, multicenter, parallel-cohort, phase 2 study. Blood. 2024;144(suppl 1):1002-1002. doi:10.1182/blood-2024-201204
2. Duan M, Ma L, Wu Q, et al. A real-world study to evaluate the efficacy and safety of selinexor in combination with ruxolitinib in patients with myelofibrosis. Hemasphere. 2023;7(53):e15697cd. doi:10.1097/01.HS9.0000971104.15697.cd
3. Selinexor in myelofibrosis refractory or intolerant to JAK1/2 inhibitors (ESSENTIAL). ClinicalTrials.gov. Updated September 10, 2024. Accessed December 10, 2024. https://clinicaltrials.gov/study/NCT03627403